Well, what can I say...I'm on a roll now!
Going back to my last thread regarding CrVI (environmental toxicity) and MS, I ended with a research article that mentioned P53 apoptosis.
Ok.....how does P53 apoptosis directly pertain to MS? Here's what I found:
J Neurochem. 2003 May;85(3):635-44. Related Articles, Links
Oligodendrocyte injury in multiple sclerosis: a role for p53.
Wosik K, Antel J, Kuhlmann T, Bruck W, Massie B, Nalbantoglu J.
Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Multiple sclerosis (MS) is a neurological disorder characterized by myelin destruction and a variable degree of oligodendrocyte death. We have previously shown that overexpression of the transcription factor p53 can induce oligodendrocyte apoptosis.
We investigated the mechanism of p53-induced apoptosis using primary cultures of central nervous system-derived adult human oligodendrocytes. Adenovirus-mediated p53 overexpression resulted in up-regulation of the death receptors Fas, DR4 and DR5 with subsequent caspase-mediated apoptosis of the oligodendrocytes.
The oligodendrocytes were protected from p53-induced cell death by blocking signaling through Fas and/or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors. Although lower levels of p53 did not induce apoptosis, the increase in death receptor expression was sufficient to render the oligodendrocytes susceptible to apoptosis in the presence of exogenous Fas ligand and TRAIL. These ligands are present in the inflammatory milieu of active MS lesions. In situ analysis of active MS lesions revealed increased p53 expression in oligodendrocytes in lesions that featured oligodendrocyte apoptosis and cell loss. Our data provide evidence for a novel role for p53 in the pathogenesis of MS.
PMID: 12694389 [PubMed - indexed for MEDLINE]
J Neurochem. 1999 Aug;73(2):605-11. Related Articles, Links
p53 induction by tumor necrosis factor-alpha and involvement of p53 in cell death of human oligodendrocytes.
Ladiwala U, Li H, Antel JP, Nalbantoglu J.
Department of Neurology and Neurosurgery, McGill University, Montreal Neurological Institute and Hospital, Quebec, Canada.
Oligodendrocytes (OLs) and their myelin membranes are the primary targets in the autoimmune disease multiple sclerosis (MS). The inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) has been implicated as a mediator of OL cell injury. TNF-alpha is detectable within MS lesions and induces apoptosis of mature human OLs in vitro. One possible mechanism by which TNF-alpha mediates cell death is through the activation of c-jun N-terminal kinase (JNK). We have previously shown that treatment of human OLs with TNF-alpha leads to activation of JNK. Here we provide evidence that p53, a regulator of the cell cycle and apoptosis, is a mediator of TNF-alpha-induced apoptosis of OLs.
Although p53 was undetectable by western blot analysis in adult human OLs, its levels increased within 24 h after TNF-alpha treatment (100 ng/ml). The induced p53 was immunolocalized to the nucleus prior to the appearance of significant numbers of apoptotic cells. Overexpression of p53 by adenovirus-mediated gene transfer into human OLs in vitro resulted in marked apoptosis as revealed by in situ cleavage of DNA (TUNEL positive), decreased mitochondrial function, and release of lactate dehydrogenase into the culture medium. These in vitro studies demonstrate that increased p53 levels are associated with apoptosis of human OLs. The findings further implicate p53 as a target for the JNK pathway activated during TNF-alpha-mediated cell death of human adult OLs.
PMID: 10428056 [PubMed - indexed for MEDLINE]
Ok.....as mentioned before in my initial research regarding desipramine, desipramine holds TNFa in check, etc. etc., and now we found that desipramine also supresses any possible CrVI activation of caspases and DNA fragmentation; not to mention we just found a connection how CrVI causes p53 apoptosis. Now we make the direct connection to what happens with p53 apoptosis, and how it affects oligodendrocytes.
And I'm having trouble getting a clinical trial performed on desipramine because............why???? Naw, I haven't found enough justification over these last few months for that, have I? HAH! Geez!!!!
No matter what "theory" you come across, desipramine shows mechanisms of action that continues to substantiate its probable effectiveness for MS therapy!